A Meta-Analysis on the Association between Peptic Ulcer Disease and COVID-19 Severity

The association between peptic ulcer disease and the severity of coronavirus disease 2019 (COVID-19) is inconclusive across individual studies. Thus, this study aimed to investigate whether there was a significant association between peptic ulcer disease and COVID-19 severity through a meta-analysis. The electronic databases (Web of Science, Wiley, Springer, EMBASE, Elsevier, Cochrane Library, Scopus and PubMed) were retrieved for all eligible studies. The Stata 11.2 software was used for all statistical analyses. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated by a random-effects meta-analysis model. The heterogeneity was evaluated by the inconsistency index (I2) and Cochran’s Q test. Egger’s analysis and Begg’s analysis were conducted to evaluate the publication bias. Meta-regression analysis and subgroup analysis were done to explore the potential source of heterogeneity. Totally, our findings based on confounding variables-adjusted data indicated that there was no significant association between peptic ulcer disease and the higher risk for COVID-19 severity (pooled OR = 1.17, 95% CI: 0.97–1.41) based on 15 eligible studies with 4,533,426 participants. When the subgroup analysis was performed by age (mean or median), there was a significant association between peptic ulcer disease and a higher risk for COVID-19 severity among studies with age ≥ 60 years old (pooled OR = 1.15, 95% CI: 1.01–1.32), but not among studies with age < 60 years old (pooled OR = 1.16, 95% CI: 0.89–1.50). Our meta-analysis showed that there was a significant association between peptic ulcer disease and a higher risk for COVID-19 severity among older patients but not among younger patients.


Introduction
Coronavirus disease 2019 (COVID- 19) was first reported in December 2019 and then rapidly spread to the rest of the world. The World Health Organization (WHO) declared the COVID-19 pandemic on 11 March 2020. The COVID-19 infection was reported to be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is an enveloped positive-sense single-stranded RNA virus belonging to the coronaviridae family, a subfamily of orthocoronavirinae. As of 1 March 2023, 758,390,564 confirmed cases of COVID-19 infection, including 6,859,093 deaths, have been reported to the WHO. It is reported that the most common clinical signs are heterogeneous and can range from entirely asymptomatic illness to mild or severe flu-like symptoms such as fever, cough, headache, sore throat, myalgia, dyspnea, vomiting, diarrhea, nausea and loss of smell and taste, to acute respiratory distress syndrome and even death [1]. Although the mortality of COVID-19 infection was reported to be 5% on average, the risk of severe/critical infection and death rises with advanced age and in the presence of several comorbidities such as hypertension, diabetes mellitus, cerebrovascular disease, cardiovascular disease, chronic respiratory illness, chronic liver disease, chronic renal disease, cancer, dementia, autoimmune disease, and so on [2][3][4][5][6][7][8][9].
Vaccines 2023, 11, 1087 3 of 14 might modify the relation between peptic ulcer disease and COVID-19 severity, the pooled effects were synthesized using the confounding variables-adjusted data in this current meta-analysis.

Materials and Methods
We performed this meta-analysis in light of the preferred reporting item for systematic reviews and meta-analysis (PRISMA) statement documented by Liberati et al. [48]. The online databases (Web of Science, Wiley Library, Springer Link, EMBASE, Elsevier Sci-enceDirect, Cochrane Library, Scopus and PubMed) were retrieved for all eligible studies as of 30 January 2023, using the keywords: ("peptic ulcer" or "digestive ulcer" or "gastric ulcer" or "duodenal ulcer" or "gastrointestinal ulcer") and ("2019-nCoV" or "COVID-19" or "SARS-CoV-2" or "2019 novel coronavirus" or "coronavirus disease 2019" or "severe acute respiratory syndrome coronavirus 2"). The outcome of interest was defined as severity (including severe/critical disease, the requirement for invasive mechanical ventilation, severity/progression, admission to the intensive care unit and death). The reference lists of the previously published review papers and the retrieved original literature were also thoroughly examined to identify all potentially relevant articles as completely as possible [49][50][51]. Two authors (Ying Wang and Jie Xu) independently performed a literature search. Any discrepancy was resolved by consulting a third author. The control group consisted of COVID-19 patients who did not have peptic ulcer disease, and the exposure group consisted of COVID-19 patients who had peptic ulcer disease.
All articles were deemed eligible for inclusion if they: (i) investigated the association between peptic ulcer disease and COVID-19 severity based on confounding variablesadjusted data; (ii) were published in English; (iii) were peer-reviewed and (iv) reported confirmed COVID-19 patients. The articles were excluded if they: (i) were review papers, animal studies, study protocol, comments, editorials, preprints, errata, duplicate literature or case reports, and (ii) reported confounding variables-unadjusted data on the association of peptic ulcer disease with COVID-19 severity.
The main information extracted from each eligible study included author name, country, study design, sample size, mean or median age, male proportion, adjusted risk factors, adjusted effect estimates and their corresponding 95% confidence interval (CI). Two authors (Ying Wang and Liqin Shi) independently performed data extraction. Any discrepancy was resolved by consulting a third author. The quality of the included studies was evaluated by investigators according to the Newcastle-Ottawa Scale (NOS) (Table S1). High-quality studies are those with scores of 8 or more, medium-quality studies with scores of 5 to 7, and low-quality studies with scores of 4 or below [52].
The Stata 11.2 software (StataCorp, College Station, TX, USA) was used to conduct all statistical analyses. The heterogeneity across the included studies was evaluated by the inconsistency index (I 2 ) and Cochran's Q test. The pooled effect size (which was presented as an odds ratio (OR)) with 95% CI was calculated by using a random-effects statistical model. Both Egger's linear regression analysis and Begg's rank correlation analysis were conducted to evaluate the possibility of publication bias. Meta-regression analysis and subgroup analysis by sample size, male proportion, study design, age, quality rating, and setting were done to explore the potential source of heterogeneity. A (two-sided) p-value of <0.05 was regarded as statistical significance.

Results
Up to 589 articles were searched in the electronic databases, and 10 additional articles were identified through the lists of references. Further, 390 duplicate articles were excluded; 156 articles were excluded after reading the titles and abstracts, and 38 articles were excluded after scanning the full texts. At last, a total of 15 eligible studies [44][45][46][47][53][54][55][56][57][58][59][60][61][62][63] consisting of 4,533,426 patients with COVID-19 were included in this meta-analysis according to the inclusion and exclusion criteria aforementioned. The flowchart of the study selection is illustrated in Figure 1. There were four studies conducted in the United States of America, were excluded after scanning the full texts. At last, a total of 15 eligible studies [44][45][46][47][53][54][55][56][57][58][59][60][61][62][63] consisting of 4,533,426 patients with COVID-19 were included in this meta-analysis according to the inclusion and exclusion criteria aforementioned. The flowchart of the study selection is illustrated in Figure 1. There were four studies conducted in the United States of America, four studies conducted in South Korea, two studies conducted in the United Kingdom, two studies conducted in Austria and one each in Spain, Croatia and Estonia. In terms of study design, there were thirteen retrospective studies and two cohort studies. The sample sizes across the included studies ranged from 1544 to 3,604,812 cases. The male proportion among the individual studies varied from 26.77% to 56.2%. The age (mean/median) among the eligible studies varied from 35.8 to 86.7 years old.
The main characteristics of the included studies are demonstrated in Table 1.  Totally, our findings based on confounding variables-adjusted data indicated that there was no significant association between peptic ulcer disease and the higher risk for COVID-19 severity (pooled OR = 1.17, 95% CI: 0.97-1.41, Figure 2A). We did not observe a significant association between peptic ulcer disease and the higher risk for COVID-19 severity in the subgroup analyses stratified by male proportion (pooled OR = 1.25, 95% CI: 0.99-1.58 for male proportion ≥ 50% and 1.13, 95% CI: 0.87-1.45 for male proportion < 50%), study design (pooled OR = 1.19, 95% CI: 0.98-1.44 for retrospective studies and 1.03, 95% CI: 0.72-1.47 for the others) and setting (pooled OR = 1.10, 95% CI: 0.98-1.22 for hospitalized COVID-19 patients and 1.22, 95% CI: 0.93-1.58 for all COVID-19 patients). When the subgroup analysis was performed by age (mean or median), there was a significant association between peptic ulcer disease and the higher risk for COVID-19 severity among studies with age ≥60 years old (pooled OR = 1.15, 95% CI: 1.01-1.32) ( Figure 2B), but not among studies with age < 60 years old (pooled OR = 1.16, 95% CI: 0.89-1.50) ( Figure 2C). Meta-regression exhibited that sample size (p = 0.111), male proportion (p = 0.691), age (p = 0.877), study design (p = 0.651), quality rating (p = 0.224), and setting (p = 0.676) might not be the potential sources of heterogeneity. Both Begg's test (p = 0.428, Figure 3A) and Egger's test (p = 0.751, Figure 3B) revealed that no potential publication bias existed in the study. 0.691), age (p = 0.877), study design (p = 0.651), quality rating (p = 0.2 0.676) might not be the potential sources of heterogeneity. Both B Figure 3A) and Egger's test (p = 0.751, Figure 3B) revealed that no p bias existed in the study.  The forest plots demonstrated that there was no significant association between peptic ulcer disease and a higher risk for COVID-19 severity (A); Subgroup analysis by age showed that there was a significant association between peptic ulcer disease and a higher risk for COVID-19 severity among studies with age ≥60 years old (B), but not among studies with age <60 years old (C). * indicates that the combined value was calculated based on data from subgroups. there was a significant association between peptic ulcer disease and a higher risk for COVID-19 severity among studies with age ≥60 years old (B), but not among studies with age <60 years old (C). * indicates that the combined value was calculated based on data from subgroups.

Discussion
Peptic ulcer disease is a frequent and dangerous disorder that can result in life-threatening consequences such as major bleeding or bowel rupture [64], and thus it is assumed to increase the risk of severity of COVID-19 patients. In this current meta-analysis based on confounding variables-adjusted data, we did not observe a signifi cant association between peptic ulcer disease and COVID-19 severity. Further subgroup analysis stratified by mean/median age revealed that peptic ulcer disease was statistically significantly related to COVID-19 severity among older patients but not among younger patients. Age has been reported to be the most important risk factor for COVID-19 severity and mortality [44,65]. A previous study by Yang et al. demonstrated that chronic liver disease was significantly independently associated with an increased risk for severity and mortality among elderly individuals with COVID-19 infection [66]. Li et al. observed that a significant association between myocardial infarction and the increased risk for COVID-19 mortality did exist among studies with patients who are ≥60 years old [2]. Ren et al. observed that peripheral artery disease significantly increased the risk for mortality among COVID-19 patients in the subgroup of patients with a mean age of ≥60

Discussion
Peptic ulcer disease is a frequent and dangerous disorder that can result in lifethreatening consequences such as major bleeding or bowel rupture [64], and thus it is assumed to increase the risk of severity of COVID-19 patients. In this current meta-analysis based on confounding variables-adjusted data, we did not observe a significant association between peptic ulcer disease and COVID-19 severity. Further subgroup analysis stratified by mean/median age revealed that peptic ulcer disease was statistically significantly related to COVID-19 severity among older patients but not among younger patients. Age has been reported to be the most important risk factor for COVID-19 severity and mortality [44,65]. A previous study by Yang et al. demonstrated that chronic liver disease was significantly independently associated with an increased risk for severity and mortality among elderly individuals with COVID-19 infection [66]. Li et al. observed that a significant association between myocardial infarction and the increased risk for COVID-19 mortality did exist among studies with patients who are ≥60 years old [2]. Ren et al. observed that peripheral artery disease significantly increased the risk for mortality among COVID-19 patients in the subgroup of patients with a mean age of ≥60 years old [67]. Oguz et al. documented that age-related immune changes might be at the bottom of the severe course of COVID-19, and age-related hormonal changes might have considerable importance due to their interactions with these immune modifications, as well as endothelial dysfunction and concomitant cardiometabolic illnesses [68]. The exact reason for the association between certain underlying diseases and COVID-19 severity among older individuals was not clear, which should be explored in the future. Similarly, Batsiou, A. et al. reviewed SARS-CoV-2 infection and outcomes in children with inflammatory bowel disease (IBD) and showed that IBD patients with SARS-CoV-2 infection did not have a more severe clinical course or disease progression [69].
In addition to patients with peptic ulcer disease, which is thought to increase the risk of severe disease in patients with COVID-19, SARS-CoV-2 infection can also cause several gastrointestinal symptoms, including diarrhea, nausea, vomiting, and abdominal discomfort [70]. A meta-analysis based on adjusted effect estimates demonstrated that gastrointestinal symptoms were not significantly associated with the risk of mortality for COVID-19 patients [71]. Current studies have shown a connection between COVID-19 infection and peptic ulcer disease. A study by Merdad et al. reported a patient who presented to the hospital with classic complaints suggestive of complicated peptic ulcer disease without any respiratory symptoms [70]. Melazzini et al.'s study showed that five patients with COVID-19 were diagnosed with peptic ulcer disease on admission without any previous history of peptic ulcer [72]. He et al. reported the case of a COVID-19 patient who developed a duodenal bulb ulcer after weeks of infection [73]. Deb et al. reported three cases of patients with COVID-19 infection who developed massive gastrointestinal bleeding from gastric ulcers during their hospitalization despite being on proton-pump inhibitor prophylaxis [74]. In addition, some other studies investigated the impact of the COVID-19 pandemic on the incidence of peptic ulcer disease. For example, research by Dao et al. observed that the proportion of peptic ulcer disease was significantly higher during the time of the state of emergency due to the ongoing COVID-19 pandemic in 2020 when compared to 2019 at the same health facility in Vietnam [75]. In line with Dao et al.'s study, Jian et al. observed that the rate of peptic ulcer disease increased dramatically in two hospitals in Wuhan, China, in 2020. They also observed an increase in the incidence of severe peptic ulcer disease after the pandemic in comparison to the same period before the pandemic [76]. The negative impact of COVID-19 on peptic ulcer disease should be focused on in the future as well.
To the best of our knowledge, this is the first study to quantitatively evaluate the association between peptic ulcer disease and the risk for COVID-19 severity by using a metaanalysis. However, some limitations should be noted in this study. Firstly, the pooled effects were synthesized by using the confounding variables-adjusted data (chiefly controlling sex, age, hypertension, diabetes mellitus, cardiovascular disease, cerebrovascular disease, renal disease, liver disease, chronic pulmonary disease, etc.), but additional confounding variables (such as types and severity of peptic ulcer disease, medications, vaccination status and SARS-CoV-2 variants) [77][78][79][80][81][82][83][84] might certainly have significant impacts on the relationship of peptic ulcer disease with COVID-19 severity. To our knowledge, none of the included studies offered details on the types and severity of peptic ulcer disease, medications, vaccination status or SARS-CoV-2 variants. This hindered us from performing further analysis to evaluate the influences of medications, types and severity of peptic ulcer disease, vaccination status and SARS-CoV-2 variants on the relationship between peptic ulcer disease and COVID-19 severity. Secondly, there was statistical heterogeneity across the included studies; thus, we performed meta-regression analysis to identify potential sources of heterogeneity, but the tested variables might not contribute to the heterogeneity. Thirdly, the included studies were mainly from South Korea and the United States of America; thus, the results were interpreted with caution in other countries or regions. Fourthly, most of the included studies were designed retrospectively; future prospective studies with large sample sizes are warranted to verify our findings.

Conclusions
Our findings based on confounding variables-adjusted data showed that there was a significant association between peptic ulcer disease and a higher risk for COVID-19 severity among older patients but not among younger patients. Further, well-designed studies with more data are required to verify our findings.

Data Availability Statement:
The data that support the findings of this study are included in this article and are available from the corresponding authors upon reasonable request.